Medicinal compositions containing 5beta - bisnorcholane-22-amino derivative as an active ingredient



United States Patent ABSTRACT OF THE DISCLOSURE This invention relatesto bacteriostatic, fungistatic and trichomonochidally activebisnorcholane derivatives with the general formula l IQ X Ca

a single or double bond with 5 beta-H configuration, and

C14-'--C2 and Co-'C likewise a single or double bond.

The preparation of the new compounds according to the invention is doneby methods known as such, in that either (a) The corresponding22-aldehyde with the general formula wherein X, Z and have the abovestated meaning, is reacted with the desired base and the double bondformed by this is reduced, if so desired with simultaneous hydrogenationof a delta double bond present in the starting material, or

3,539,687 Patented Nov. 10, 1970 -(b) The carbonyl oxygen of the amidegroup in compounds with the formula V T U 04 wherein R R Z, X and havethe above mentioned meaning, is reduced to a CH group, whereby if sodesired a 3-keto group present in the starting produce is previouslyprotected provisionally, or

(c) Compounds with the formula CHzOH wherein Z,

and X have the above mentioned meaning, are esterified in the22-position with a sulfo-acid and the resultant 22- ester is reactedwith the desired base, or

(d) The ZZ-sulfo-acid ester prepared according to technique in above (0)is converted in the usual manner known as such, into the 22-halogencompound, preferably the 22-iodoor 22-bromo compound, and it reactedwith the finally desired base and in the products prepared according totechniques in above (a), (b), (c) and (d), if so desired, an 11- or 3-OHgroup present in the starting produce or formed in the course of thereaction is subsequently acylated or oxidized or a 3-O-acyl group issaponified or an 11- and/or 3-keto group and/or delta double bond isreduced or in the presence of a delta double bond if so desired anadditional delta and/or delta double bond is introduced, or the 22-aminogroup formed is monoor dialkylated with R and /or R meaning hydrogen,and the primary product thus obtained converted if so desired into thecorresponding secondary, tertiary or quarternary ammonium salt.

The technique (a) of the procedure according to the invention is forexample so executed that the corresponding 22-aldehydes are reacted withthe customarily usable primary or secondary amines, such as possiblysubstituted monoor dialkylamines, monoor diarylamines, alkylarylamines,such as methylaniline, ethylaniline, as Well as possibly withsubstituted piperidine, morpholine, pyrrolidine or the like. When basesare used in which neither R nor R designates a hydrogen atoms, then oneobtains in this condensation products in which the double bond formed isin the 20(22) position. If, however, bases are used for the condensationreaction in which R and/0r R designates hydrogen, then one obtainscondensation products With a C N double bond. The subsequent reductionof the double bond formed takes place according to working methods,known as such. The hydrogenation in the presence of the customary metalcatalysts, such as for example platinum oxide, is generally suitable.But the reduction can also be carried out according to known chemicalworking methods, such as for example, by means of formic acid. The @Ndouble bond, however, is also reducible for example with hydrides, suchas lithium aluminum hydride or sodium boron hydride.

The reduction of the carbonyl oxygen atom of the amide group as intechnique (b) above, is carried out according to the methods and withthe reducing agents that are known to the specialist for the reductionof acid amides to the corresponding amines. Preferred suitable reducingagents are in particular lithium aluminum hydride, aluminum alkylcompounds, such as diisobutyl aluminum hydride and other complex metalhydrides. In this, the starting product is reacted in a suitable inertsolvent, such, as for example, tetrahydrofuran, dioxan, ether, benzeneand others, with the reagent at preferably increased reactiontemperature, and if so desired with the exclusion of atmospheric oxygen,nitrogen or argon are preferably suitable is protective atmosphere orblanket.

If the compounds according to the invention are to be prepared bytechnique above, then the substitution of the previously introduced22-sulfo-acid ester, preferably of the 22-mesyl or 22-tosyl residue,occurs through the finally desired amino group likewise according tomethods, known as such in the art. The exchange expediently takes placein such a way that for example, the corresponding 22-mesyl or -tosylester in a suitable solvent, such as for example, benzene, is reactedwith the desired base, which may also be a solvent at the same time, atpreferably increased reaction temperature. It may be expedient in somecases here to convert the 22-sulfo-acid ester in a manner known as such,first into the corresponding 22- halogen, preferably iodo or bromocompound, for example, by means of alkali halides, such as sodiumiodide, in an anhydrous solvent, which is then reacted with the finallydesired base. The procedural modification is preferably applicable t'orthe production of the 3-ketoor 3-ketodelta -compounds, because in thepresent case the protection of the 3-keto group needed for exampleaccording to the technique (a), or the later oxidation of a hydroxylgroup in the 3-position can be saved.

The subsequent introduction, if it is desired, of the delta and/or delta-double bond likewise takes place according to methods known as suchpreferably by means of selenious acid (delta -double bond) or by meansof dichlorodicyano-benzoquinone or chloranil (deltaand if so desiredfollowed by delta -double bond).

The salt formation takes place with all acids or organic halides, whichcustomarily form ammonium salts with the above mentioned bases, such asmineral acids, organic acids, alkyl halides, such as for example methyliodide.

Listed by way of example, the purposes herein are the following acids:Hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, aceticacid, butyric acid, caproic acid, oxalic acid, succinic acid, benzoicacid and the like. As oxidation methods can be considered all thosesuitable for the conversion of a 3-OH group into the 3-keto group, suchas for example the method according to Oppenauer.

It is known (H. L. Herzog, Am. Soc. 77 (1955), p. 5324), that delta-bisnorcholane and 5 alpha-bisnorcholane derivatives are effectiveagainst Candida albicans.

It has now been found that the ZZ-N-substituted bisnorcholanederivatives of the above cited formula according to the invention arenot only effective against Candida albicans, but also againstStaphylococci, Klebsiella pneumoniae, bacteria of the Proteus group,pathogenic yeasts as well as particuarly against Dermatophytes andTrichomonades, which is particularly advantageous in combatting mixedinfections.

The excellent fungicidal action is to be shown by the example ofZZ-(N-piperidyl) 5 beta bisnorcholane 3 alpha-olhydrochloride (I) and of22-(N-piperidyl)-5 betabisnorcholane-3-one hydrobromide (II) compared tothe known Griseofulvin, whereby the indicated concentrations reproducethe dosage at which total growth inhibition occurs in vitro as indicatedherein following:

AMicr0sp0rum gypsum, concentration gamma/ ml. B-Trichophyt0nmentagrophytes var. persicolor, concentration gamma/ml.

Preparation A B Griseofulvin 50 200 I 5 10 II 1O 50 From this is canalso be seen that micro-organisms which already show resistance toGriseofulvin, can still be combatted or affected by the compoundsproduceable according to the invention. The compounds that can beprepared according to the invention are thus also still suitable forcombatting those strains which are resistant to other bacteriostaticallyactive substances.

22 N amino 5 alpha-bisnorcholane hydrochloride proves to be fullyeffective at 1 gamma/ ml. against M icrococcus pyogenes aureus (strain127a). Erthyromycin acts against this strain with 5 gamma andStreptomycin with 10 gamma/m1.

The compounds according to the invention serve for the externalparenteral or oral treatment of for example, the following afflictions:Dermatomycoses, septic conditions, pneumonias, urinary passageinfections, etc. They are in particular also well suited for thetreatment of mixed infections.

Some of the new compounds according to the invention are alsodistinguished by a strong infiamation-inhibiting effect. A specificexample is 22-N-piperidyl-delta bisnorcholene-ll beta-Ol-3-one.

The compounds can be put into the prepared forms customary inpharmacology, and may be applied by injection as well as per se or forexample locally as a salve. For the peroral application, the manufactureof the substances can be done with or without the additives, carriersubstances, taste correcting agents and the like customary in galenicalpharmacology, for example in the form of a powder, as tablets,sugar-coated pills, capsules or pills.

The preparation of the starting products, which have not been describedpreviously, for which no protection is claimed within the frame of thepresent invention, is conducted according to methods known as such inthe art, for example, from the corresponding 22-aldehydes. For thepreparation of the starting products according to technique (b) theseare oxidized to the corresponding 22- carbonic acids, which converted,likewise in a manner known as such in the art, through the corresponding22- acid chlorides into the desired 22-amides, and for the preparationof the starting products according to technique (c) the 22-aldehydes arereduced to the corresponding 22-alcohols. Y

The following examples are illustrative of the invention, withoutrestriction thereto.

EXAMPLE 1 (a) 5 gm. of 3 alpha-acetoxy 22 (N piperidyl)- delta-5-bisnorcholane, prepared analogously to Example 3(a) are dissolved in350 ml. of glacial acetic acid and hydrogenated with 500 mg. platinumoxide as a catalyst. After this, the product is suctioned from theresultant catalyst, the filtrate is stirred into ice water and reactedto weakly alkaline reaction. The hydrogenated reaction productfiocculates out during this, and is then isolated with methylenechloride. The methylene chloride phase, washed with water and dried withsodium sulfate, is evaporated to dryness under reduced pressure and oneobtains 4.8 gm. of 3 alpha-acetoxy-2-(N-piperidyl) 5betabisnorchlo-olane.

(b) 4.8 gm. of 3 alpha-acetoxy 22-(N-piperidyl)-5- beta-bisnorcholaneare heated with 250 ml. of 4% solution of potassium hydroxide for hourunder reflux. After cooling, the reaction mixture is stirred into icewater and the saponification product is isolated by extracq tion withmethylenechloride. The methylenechloride extracts washed with water anddried over sodium sulfate after evaporation under diminished pressureyield 4.55 gm. 22- (n-piperidyl) --beta-bisnorcholane-3-alpha-ol) (c) Byintroducing hydrogen chloride gas into a solution of 4.55 gms. of22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1 in about 200 mls. ofether there separate out 4.8 gm. of 22-(N-piperidyl)-5beta-bisnorcholane-3- alpha-ol-hydrochloride as a white, crystallineprecipitate, which after being suctioned, washed with ether and dried,melts at 249/ 254-260 deg. C.

Analysis.--Calculated for C H ClNO (percent): N, 3.20; Cl, 8.10. Found(percent): N, 3.44; CI, 8.12.

EXAMPLE 2 (a) 660 mg. of 22-(N-piperidyl)5 beta-bisnorcholane-3-alpha-ol are dissolved in 86 ml. toluene and reacted with 2.06 ml. ofcyclohexanone. After this, one distills until a clear distillate isobtained. A solution of 163 mg. aluminum is o-opropylate in 5 ml.toluene is added to the boiling solution and one heats for 40 minutesunder reflux. After cooling to 50 C., 945 mg. of Rochelle salt in 1 ml.water are added and the mixture is stirred for 1 hour. Then it isdistilled with steam until no more oil comes over. After the reactionmixture has cooled to 50 C., it is stirred for /2 hour after addition of0.6 ml. of glacial acetic acid. The oxidation product is isolated byextraction with toluene. The toluene phase is washed neutral with water,dried with sodium sulfate and concentrated under reduced pressure. Oneobtains 370 mg. 22- (N-piperidyl)-5 beta-bisnorcholane-3-one.

(b) By introducing hydrogen chloride into a solution of 370 mg. of22-(N-piperidyl)-5 beta-bisnorcholane-3- one in about 50 ml. ether,there separate out 400 mg. 22 (N-piperidyl)-5beta-bis-norcholane-3-one-hydrochloride as a white, crystallineprecipitate, which after drying in vacuum melts at 254/ 268-271 deg. C.

Analysis.Calculated for C27H45C1N0 (percent): N, 3.22; CI, 8.15. Found(percent): N, 3.18; Cl, 8.25.

EXAMPLE 3 (a) A solution of 15.8 gm. of 5 beta-bisnorcholane-22- al, 64mg. p-toluene-sulfo-acid and 7.5 ml. of freshly distilled piperidine in375 ml. of absolute benzene are heated for 3 hours under reflux, using awater separator. After cooling the benzene phase is washed several timeswith water, dried with sodium sulfate and evaporated under reducedpressure. After recrystallization from acetone, one obtains 17.3 gm. of22-(N-piperidyl)-delta (22)-5 beta-bisnorcholene with a melting point of104/ 106- 109 C.

(b) 4 gm. of 22-(N-piperidyl)-delta -5 beta-bisnorcholane are dissolvedin 300 ml. glacial acetic acid and hydrogenated with 400 mg. of platinumoxide as a catalyst. After this, the reaction product is suctioned fromthe catalyst, the filtrate is stirred into ice water and reacteddropwise while stirring with dilute sodium hydroxide up to a weaklyalkaline reaction. The hydrogenated reaction product flocculates orseparates out during this, which is isolated with methylenechloride. Themethylenechloride phase washed with water and dried with sodium sulfateis concentrated to dryness under reduced pressure and one obtains 3.8gm. 22-(N-piperidyl)-5 beta-bisnorcholane.

(o) By introducing hydrogen chloride into a solution of 3.8 gm. of22-(N-piperidyl)-5 beta-bisnorcholane in about 150 ml. ether, thereseparate out 4.1 gm. 22-(N- piperidyl)-5beta-bis-norcholane-hydrochloride as a white, crystalline precipitate,which after drying in vacuum melts at 264/269-275" C.

Analysis-Calculated for C H ClN (percent): N, 3.32; Cl, 8.40. Found(percent): N, 3.33; Cl, 8.40.

EXAMPLE 4 (a) A solution of 5 gm. 3 alpha-acetoxy-Sbeta-bisnorcholane-22-al, 21 mg. p-toluene sulfo-acid and 2.5 ml.

freshly distilled morpholine in ml. absolute benzene are heated for 3hours under reflux, using a water separator. After cooling, the benzenephase is washed several times with water, dried with sodium sulfate andconcentrated under reduced pressure. One obtains 5.5 gm. of 3alpha-acetoxy-ZZ (N-morpholino)-delta -5 beta-bisnorcholane.

Analysis-Calculated for C H NO (percent): N, 3.16. Found (percent): N,3.11.

(b) 5.5 gm. of 3 alpha-acetoxy 22-(N-morpholino)- delta -5beta-bisnorcholane are dissolved in 350 ml. of glacial acetic acid andhydrogenated with 550 mg. of platinum oxide as catalyst. After this, thereaction product is suctioned from the catalyst the filtrate stirredinto ice water and reacted dropwise while stirring with dilute sodiumhydroxide up to a weakly alkaline reaction. In this, the hydrogenatedreaction product flocculates or separates out, which is isolated withmethylenechloride. The methylenechloride phase washed with water anddried with sodium sulfate is evaporated to dryness under reducedpressure and one obtains 5.2 gm. 3 alpha-acetoxy- 22- (N-morpholino -5beta-bis-norcholane.

(c) By introducing hydrogen chloride into a solution of 5.2 gm. of 3alpha-acetoxy-ZZ-(N-morpholino)-5 betabisnorcholane in about 200 ml.ether there separate 5.5 gm. of 3 alpha-acetoxy-22 (N-morpholino)-5beta-bisnorcholane-hydrochloride as a white, crystalline precipitate,which after drying in vacuum melts at 235/240- 248 deg. C.

Analysis.Calculated for C H ClNO (percent): N,

2.91; Cl, 7.38. Found (percent): N, 2.87; Cl, 7.31.

(d) 3.6 gm. 3 alpha-acetoxy 22-(N-morpholino)-5 beta-bisnorcholane areheated with ml. of 4% solution of methanolic potassium hydroxide for 4hour under reflux. The reaction mixture is stirred into ice water andthe saponification product is isolated by extraction withmethylenechloride. The methylenechloride extracts are washed neutralwith water and dried with sodium sulfate. After evaporation underdiminished pressure, the yield is 3.4 gm. 22-(N-morpholino)-5beta-bisnorcholane-3 alpha-o1.

(e) By introducing hydrogen chloride into a solution of 3.4 gm. of22-(N-morpholino)-5 beta-bisnorcholane-3 alpha-o1 in about 150 ml. ofether, there separate 3.8 gm. of 22-(N-morpholino)-5beta-bisnorcholane-3 alpha-olhydrochloride as a white, crystalline,precipitate, which after drying in vacuum melts at 235 /240250 C.

Analysis.Calculated for C H CINO (percent): N, 3.18; CI, 8.06. Found(percent): N, 3.02; C], 8.16.

EXAMPLE 5 (a) A solution of 5 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane-22-al, 25 mg. p-toluene sulfo-acid, 2.5 ml. freshlydistilled pyrrolidine in 120 -ml. absolute benzene are heated for 3hours under reflux, using a water separator. After cooling, the benzenephase is washed several times with water, dried with sodium sulfate andconcentrated under reduced pressure. One obtains 4.3 gm. of 3alpha-acetoxy-ZZ-(N-pyrrolidine)-de1ta -5 beta-bisnorcholene.

(b) 4.3 gm. of 3 alpha-acetoxy-ZZ-(N-pyrrolidino)-delta -bisnorcholeneare dissolved in 300 ml. gacial acetic acid and hydrogenated with 450mg. platinum oxide as catalyst. After this, the reaction product issuctioned from the catalyst, the filtrate is stirred into ice water andreacted dropwise while stirring with dilute sodium hydroxide up toweakly alkaline reaction. In this, the hydrogenated reaction productflocculates, or separates which is isolated with methylenechloride. Themethylenechloride phase is washed neutral with water and dried withsodium sulfate and is concentrated to dryness under reduced pressure.One obtains 3.7 gm. of 3 alpha-acetoxy- 22- (N-pyrrolidibo) -5beta-bisnorcholane.

(c) 3.7 gm. of 3 alpha-acetoxy-ZZ-(N-pyrrolidino)-5 beta-bisnorcholaneare heated with 180 ml. of 4% solution of methanolic potassium hydroxidefor /4 hours under reflux. After cooling, the reaction mixture isstirred into ice water and the saponification product is isolated byextraction with methylenechloride. The methylenechloride extracts arewashed neutral with water and dried with sodium sulfate, and afterconcentration under diminished pressure yield 3.24 of gm.22-(N-pyrrolidino)-5 beta-bisnorcholane-3 alpha-o1.

(d) By introducing hydrogen chloride gas into a solution of 3.24 gm. of22-(N-pyrrolidino)-5 beta-bisnorcholane-3 alpha-o1 in about 150 ml.ether there separate out 3.4 gm.33-(N-pyrrolidino)-5beta-bisnorcholane-3 alpha ol-hydrochloride as aWhite crystalline precipitate, which after drying in vacuum melts at230/23 8248 C.

Analysis.-Calculated for C H ClNO (percent): N, 3.30; Cl, 8.36. Found(percent): N, 3.16, Cl, 8.36.

EXAMPLE 6 (a) A solution of 5 gm. 3 alpha-acetoxy-5beta-bisnorcholane-22-al, 21 mg. of p-toluene sulfo-acid, 50 ml. offreshly distilled diethylamine and 50 ml. of absolute ether is heatedfor about 8 hours under reflux. After cooling, the reaction solution isfiltered, washed several times With water, dried with sodium sulfate andconcentrated under reduced pressure. One obtains 4.2 gm. of 3alpha-acetoxy- 22-(N-diethylamino)-delta -5 beta-bisnorcholene.

Analysis.-Calculated for C H N (percent): N, 3.26. Found (percent): N,3.23.

(b) 4.2 gm. 3 alpha-acetoxy-22-(N-diethylamino)- deltabeta-bisnorcholene are dissolved in 300 ml. of glacial acetic acid andhydrogenated with 450 mg. platinum oxide as catalyst. After this, thereaction product is suctioned from the catalyst, the filtrate is stirredinto ice water and reacted drop'wise While stirring with dilute sodiumhydroxide up to weakly alkaline reaction. In this, the hydrogenatedreaction product flocculates or separates out, which is isoluated withmethylenechloride. The methylenechloride phase is washed neutral withwater and dried with sodium sulfate. It is concentrated to dryness underreduced p-ressue. The product is 3.6 gm. 3alpha-acetoxy-22-(N-diethylamino)-5 beta-bisnorcholane.

(c) 3. 6 gm. 3 alpha-acetoxy122-(N-diethylamino)-5 beta-bisnorcholaneare heated with 180 ml. of 4% solution of methanolic potassium hydroxidefor hours under reflux conditions. After cooling, the reaction mixtureis stirred into ice water and the saponification product is isolated byextraction with methylenechloride. The methylenechloride extracts arewashed neutral with Water and then dried with sodium sulfate. Afterconcentration under reduced pressure the yield is 3.1 gm.22-(N-diethylamino)-5 beta-bisnorcholane-3 alpha-o1.

(d) By introducing hydrogen chloride into a solution of 3.1 gm. of22-(N-diethylamino)-5 beta-bisnorcholane-3 alpha-o1 in about 150 ml.ether there separate 3.2 gm. 22- (N-diethylamino)-5 beta-bisnorcholane-3alpha-ol-hydrochloride as a white, crystalline precipitate, which afterdrying in vacuo melts at 1'80/186192 C.

Analysis.-Calculated for C H ClNO (percent): N, 3.29; Cl, 8.32. Found(percent): N, 3.10; Cl, 7.96.

EXAMPLE 7 (a) 6.45 gm. 3 alpha-acetoxy-S beta-bisnorcholane-22 acid aresuspended in 135 m1. anhydrous benzene, reacted with 3.2 ml.thionylchloride and 0.1 ml. pyridine and stirred for one hour at roomtemperautre. The clear reaction solution is then concentrated to drynessunder reduced pressure whereby 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid chloride is obtained which can be processedfurther in this form without further purification.

(b) 6.75 gm. of crude 3 alpha-acetoxy-S beta-bisnorcholane-22-acidchloride are dissolved in 200 ml. tetrahydrofurane, filtered from aprecipitated contamination and the clear solution thus obtained isdropped with stirring and ice cooling into 200 ml. of aqueous ammonia.The mix is diluted with 2 liter ice water, and the resultantprecipirate, 3 alpha-acetoxy-5 beta-bisnorcholane-2-2-acid amide issuctioned off, washed, dried and recrystallized from isopropanol. Oneobtains 5.26 gm. with M.P. 188.5 189.5 C.

(c) 4 gm. of 3 alpha-acetoxy-S beta-bisnorcholane-22- acid amide aredissolved in 65 ml. tetrahydrofurane and dropped with stirring in to 'aslurry of 1.5 gm. lithium aluminum hydride in 65 ml. of ether.Subsequently, the reaction mixture is heated with stirring and undernitrogen for about twenty hours under reflux. The mix is allowed to cooland the excess lithium aluminum hydride is decomposed with acetone. ml.of Water are then added, the precipitate which has come down issuctioned off, re- Washed with ether and methylenechloride and theorganic phase is separated, washed, dried and concentrated to dryness.The yield is 3.25 gm. of 22-amino-5 beta-bisnorcholane-3 alpha-o1 withM.P. 197198 C.

(d) Into a solution of 1.5 gm. of 22-amino-5 betabisnorcholane-3alpha-o1 in dry ether dry hydrogen chloride is introduced with stirringand ice cooling. The precipitated 22-amino-5-beta-bisnorcholane-3alpha-ol-hydrochloride is suctioned off and dried. One obtains 1.4 gm.'with M.P. 332334 C. (decomposition) EXAMPLE 8 (a) 1.5 gm. 3alpha-acetoxy-S beta-bisnorcholane-22- acid are converted similarly asin example 7 into 3 alphaacetoxy-S beta-bisnorcholane-22-acid chloride.The acid chloride thus obtained is then dissolved in 30 ml. of benzeneand put into a solution of 2 ml. piperidine in 10 ml. benzene. Thereaction solution is then left to stand at 50 C. for one hour. Afterthis, it is allowed to cool to room temperature and diluted With 60 ml.benzene. The reaction mixture is then poured into 300 ml. ice water, thebenzolic phase is separated, washed with water, 2 n HCl and water, driedover sodium sulfate and concentrated to dry ness under diminishedpressure. The residue, after filtration over a 10-fold quantity ofsilica gel is recrystallized from hexane. One obtains 1.3 gm. of 3alpha-aceotxy-S beta-bisnorcholane-22-acid piperidide with M.P. 151.5-152 C.

(b) 1.3 gm. of 3 alpha-acetoxy-S beta-bisnorcholane- 22-acid piperidideare dissolved in 40 ml. of tetrahydrofurane, poured into a suspension of0.4 gm. lithium aluminum hydride in 30 ml. ether and treated further andprocessed similarly to Example 7 (c). The resultant 22- (N-piperidyl)-5beta-bisnorcholane-3 alpha-o1 is recrystallized from hexane. One obtains1.1 gm. with M.P. l53- 154 C.

(c) Into a solution of 1.5 gm. of 22-(N-piperidyl)-5beta-bisnorcholane-3 alpha-o1 in 120 ml. of dry ether are introducedwith stirring and ice cooling, dry hydrogen chloride in excess. Theresultant precipitate is suctioned off, washed with ether and dried.1.55 gm. of 22-(N- piperidyl)-5 beta-bisnorcholane-3 alpha-o1hydrochloride with M.P. 324326 C. (decomposition) are obtained.

((1) To mg. of 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1 in 10ml. ether is added a solution of 37.8 mg. salicylic acid in 2 ml. ether.The reaction mixture is stirred for one hour at room temperature. Afterthis, the resultant precipitate is suctioned off, washed two times with2 ml. ether and dried. 108 mg. of 22-(N- piperidyl)-5beta-bisnorcholane-3 alpha-ol-salicylate with M.P. 19 8200 C.(decomposition) are obtained.

(e) 0.3 gm. of 22-(N-piperidino)-5 beta-bisnorcholane-3 alpha-o1 areheated with 3 ml. of methyliodide for one hour under reflux. After this20 ml. of methanol are added and heated for an additional hour underreflux. Subsequently, the mix is concentrated to dryness under reducedpressure and the residue recrystallized from ethanol. 240 mg.22-(Npiperidino)-5 beta-bisnorcholane-3 alpha-o1 methiodide with M.P.283 C. (decomposition) are obtained.

EXAMPLE 9 (a) Similarly to Example 7(a) one obtains the-betabisnorchlorane-3-one-22-acid chloride from 2 gm. 5betabisnorcholane-3-one-22-acid. This is then reacted analogously toExample 8(a), with piperidine into 5 beta-bisnorcholane-3-one-22-acidpiperidide, which after reduction with lithium aluminum hydride underthe conditions of Example 8(b), yields 0.6 gm. of mixture of 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1 and 22-(N- piperidyl) 5beta-bisnorcholane-3 beta-o1.

(b) 0.6 gm. of mixture of 22-(N-piperidyl)-5 beta-bisnorcholane-3alpha-o1 and 22-(N-piperidyl)-5 beta bisnorcholane-3 beta-o1 aredissolved in 86 ml. toluene and reacted with 2.06 ml. cyclohexanone.Subsequently this is distilled until a clear distillate comes over. Tothe boiling solution is added a solution of 0.6 gm. of aluminumisopropylate in 5 ml. toluene. This all is heated for 40 minutes underreflux. After cooling to 50 C. one adds 0.95 gm. Rochelle salt in 1 ml.Water and stirs for one more hour. Then one distills with steam until nomore oil comes over. After the reaction mixture has cooled to 50 C., onestirs for /2 hour after the addition of 0.6 ml. glacial acetic acid. Theoxidation product is washed neutral with water, dried over sodiumsulfate and concentrated under diminished pressure. Afterrecrystallization from isopropanol/ water solution one obtains 0.39 gm.22-(N-piperidyl)-5 beta-bisnorcholane-3-one with M.P. 114-115 C.

(c) By introducing hydrogen chloride into a solution of 0.37 gm.22-(N-piperidyl)5 beta bisnorcholane-3-one in ether there separate out0.4 gm. of 22-(N-piperidyl)-5 beta-bisnorcholane-3-one hydrochloride asa white crystalline precipitate, which after being suctioned and driedmelts at 290296 C. (decomposition).

EXAMPLE 10 0.66 gm. of 22-(N-piperidyl)5 beta-bisnorcholane-3 alpha-o1are oxidized analogously to Example 9(b) and processed. Afterrecrystallization from isopranol/water solution, 0.45 gm. ofZZ-(N-piperidyU-S beta-bisnorcho- 1ane-3-one with M.P. 114-115 C. areobtained.

EXAMPLE 11 (a) The 3 alpha-acetoxy-S beta-bisnorcholane-Z2-acid chlorideobtained analogously to Example 7(a) from 2 gm. 3 alpha-acetoxy-Sbetabisnorcholane-22-acid is dissolved in ml. of benzene and added to asolution of 2 gm. of aniline in 10 ml. of benzene. The reaction mixtureis then left at C. for one hour with stirring and allowed to cool. Aftercooling the mix is stirred and poured into water. The organic phase isseparated, washed with water, dilute hydrochloric acid and again withwater, dried over sodium sulfate and the solvent is distilled off underreduced pressure. The residue is recrystallized from isopropanol and oneobtains 1.8 gm. 3 alphaacetoxy-S beta-bisnorcholane-22-acid anilide withM.P. 260262 C.

(b) 1 gm. 3 alpha-acetoxy-S beta-bisnorcholane-22- acid anilide isreduced with lithium aluminum hydride in a manner similar to Example 7(c) and processed. One obtains 2-phenylamino-5 beta-bisnorcholane-3alpha-ol.

(c) 0.2 gm. crude 22-phenylamino-5 beta-bisnorcholane-3 alpha-o1 aredissolved in 30 ml. tetrahydrofuran and saturated at 0 C. with dryhydrogen chloride gas. After the solution stands overnight the22-phenylamino5 beta-bisnorcholane-3 alpha-o1 hydrochloride crystallizesout, which is suctioned off, washed with ether and dried. One obtains0.11 gm. with M.P. 245247C. (decomposition).

EXAMPLE 12 In a manner similar to Example 8(a), the 3 alpha-acetoxy-5beta-bisnorcholane22-acid chloride obtained from 1.5 gm. 3alpha-acetoxy-S beta-bisnorcholane-22-acid is converted with 2 ml. ofmorpholine into the 3 alpha-acetoxy-S beta-bisnorcholane-22-acidmorpholide, which is reduced analogously to Example 8(b) to22-(N-morpholino)-5 beta-bisnorcholane-3 alpha-o1. From this one obtainsanalogously to Example 8(c) 0.8 gm. 22-(N-morpholino)-5beta-bisnorcholane-3 alpha-o1 hydrochloride with M.P. 240250 C.

EXAMPLE 13 In a manner similar to Example 8(a), the 3 alpha-acetoxy-5beta-bisnorcholane-22-acid chloride obtained from 1.5 gm. 3alpha-acetoxy-S beta-bisnorcholane-ZZ-acid is converted with 2 ml.pyrrolidine into the 3 alpha-acetoxy-5 beta-bisnorcholane-Z-acidpyrrolidine, which is reduced analogously to Example 8(b), to the22-(N-pyrrolidino)-5 beta-bisnorcholane-3-alpha-ol. From this areobtained, analogously to Example 8(b) 0.75 gm. of 22- (N pyrrolidino)-5beta-bisnorcholane-3 alpha-ol-hydrochloride with M.P. 238248 C.

EXAMPLE 14 In a manner similar to Example 8(a), the 3 alphaacetoxy-Sbeta-bisnorcholane-22-acid chloride obtained from 1.5 gm. 3alpha-acetoxy-S beta-bisnorcholane-22- acid is converted with 2 ml.diethylamine into the 3 alphaacetoxy-S beta-bisnorcholane-22-aciddiethylamide, which is reduced, analogously to Example 8(b), to the22-(N- diethylamine)-5 beta-bisnorcholane- 3 alpha-o1. From this, arethen obtained analogously to Example -8(c), 0.76 of gm.22-(N-diethylamino)-5 beta-bisnorcholane-3 alpha-o1 hydrochloride withM.P. 186192 C.

EXAMPLE 15 (a) Analogously to Example 7(a), 3 gm. of 5betabisnorcholane-ZZ-acid (M.P. 209211 0., prepared from 5beta-bisnorcholane-22-al by oxidation with chromic acid) are convertedto 5 beta-bisnorcholane-ZZ-acid chloride, which is then reactedanalogously to Example 7(b) with ammonia and processed. Afterrecrystallization from isopropylether of 2.4 gm. of 5beta-bisnorcholane- 22-acid amide with M.P. 200-200.5 C. are obtained.

(b) 1 gm. of 5 beta-bisnorcholane-22-acid amide is reduced, analogouslyto Example 7(c), and processed. After recrystallization fromisopropanol/water, 0.7 gm. of 22-amino 5 beta-bisnorcholane with M.P.113-115 C. are obtained.

(0) Analogously to Example 7(d), 0.155 of gm. 22- amino-5beta-bisnorcholane-hydrochloride with M.P. 295300 C. (decomposition) areobtained from 0.15 gm. 22-amino-5 beta-bisnorcholane.

EXAMPLE 16 The 5 beta-bisnorcholane-Z2-acid chloride as obtainedanalogously in Example 15 (a) from 2.5 gm. of 5betabisnorcholane-ZZ-acid is converted in a manner analogous to Example8(a) with 2.5 ml of piperidine into the 5 beta-bisnorcholane-ZZ-acidpiperidide and reduced further similar to Example 8(b) with lithiumaluminum hydride and processed. The crude 22-(N-piperidyD-5-beta-bisnorcholane thus obtained is dissolved in ether and the22-(N-piperidyl)-5 beta-bisnorcholane-hydrochloride is precipitated byintroducing hydrogen chloride. After suctioning and drying, 1.6 gm. withM.P. 269- 275 C. are obtained.

EXAMPLE 17 (a) 1 gm. delta -bisnorcholene-22-ol-3-one are dissolved in12 ml. pyridine, reacted with a solution of 2 gm. of p-toluenesulfochloride in 2 ml. pyridine while cooling with ice, and allowed tostand for 2 hours at room temperature.

For processing, the reaction mixture is stirred with dilute hydrochloricacid, and the resultant precipitate is suctioned off, washed first withdilute hydrochloric acid, and then continued to neutrality with water.After recrystallization from acetone 960 mg. delta -bisnorcholene-22-01-3-one-22-p-tosylate are obtained which melts at 167172 C.

(b) 100 mg. of delta -bisnorcholene-22-ol-3-one-22- p-tosylate aredissolved in a mixture of 1 ml. of piperidine and 1 ml. of acetone andleft to stand at room temperature overnight.

-For processing, this mixture is stirred with dilute hydrochloric acid,the hydrochloric acid solution is extracted several times with ether,then made alkaline with dilute sodium hydroxide and the precipitatedproduct is extracted with ether. The ether phase, after it is washedneutral and dried over sodium sulfate, is concentrated to dryness. Thecrude product after recrystallization from ethanol/water yields 80 mg.of 22-(N-piperidyl)-delta bisnorcholene-3-one with melting point 160162C.:

UV: Epsilon :16,000.

(c) In a manner similar to Example 8(c), 87 mg. 22 (N-piperidyl)-delta-bisnorcholene 3 one-hydrochloride with M.P. 286288 C. (decomposition)are obtained from 100 mg. of 22-(N-piperidyl)-delta -bisnorcholene-3-one;

UV: Lambda =242 m-mu, epsilon=15,000.

EXAMPLE 18 200 mg. of 22-amino-5-beta-bisnorcholane-3 alpha-o1 aredissolved in 5 ml. ether and 166 mg. of 1,5-dibromopentane and 140 mg.of anhydrous sodium carbonate are added. The reaction mixture is heatedfor 16 hours with stirring and under reflux. The resultant mix isallowed to cool. 20 ml. of ethanol are added and the inorganiccomponents are suctioned off. The filtrate is concentrated to drynessand the residue obtained is dissolved in ether. The insoluble residue issuctioned and the other solution concentrated to dryness. The22-(N-piperidyl)-5 betabisnorcholane-3 alpha-o1 which resmains behind isrecrystallized from hexane. 120 mg. with a M.P. 153-154" C. areobtained.

EXAMPLE 19 (a) A mixture of 11.8 gm. of bisnor-S beta-cholane-3alpha-ol-22-al-3-acetate, 285 ml. of benzene, 5.9 ml. of freshlydistilled piperidine and 50 mg. p-toluo-sulfo-acid are heated for 3hours under reflux with a water separator. After cooling about /2 literwater are added and shaken through. The benzene phase is then separatedand washed neutral with water. After drying over sodium sulfate andfiltering, it is concentrated in vacuum. One obtains 11.35 gm.substance. This paste is stirred cold with methanol, suctioned off anddried. One thus obtains 5.60 gm. of 22-(N-piperidyl)-delta -bisnor-5beta-cholane-3 alpha-ol-3 acetate with M.P. 108111 C.

(b) The 5.60 gm. enamine from (a) are dissolved in 26 ml. of absolutebenzene and dripped with stirring into 185 ml. ether saturated with HCl.The precipitated hydrochloride is carefully suctioned off and wellwashed with ether and dried. One obtains 4.43 gm. enaminehydrochloridewith M.P. 11l113 C. (decomposition).

(c) The 4.43 gm. enamine-hydrochloride from (b) are dissolved in about 1liter water allowed to stand overnight. A substance precipitates duringthis. After suctioning and drying, one obtains 3.42 gm. of 20alphabisnor-5 beta-cholane-3 alpha-ol-22-al-3-acetate, which afterrecrystallization from isopropylether melts at 119- 120 C.; (alpha) 49(CHCl (d) 3.20 gm. of 20 alpha-bisnor-S beta-cholane-3alpha-ol-22-al-3-acetate are hydrogenated in 200 ml. ethanol in thepresence of Raney nickel catalyst.

After the hydrogen absorption is concluded, the product is then filteredfrom the catalyst under nitrogen and the filtrate is concentrated invacuum. There are obtained 3.2 gm. of crude product (M.P. 103l07 C.).After recrystallization with isopropylether 20 alph-bisnor- 5beta-cholane-3 alpha, 22-diol-3-acetate is obtained, having a meltingpoint 1145-116 C.

(e) 1.70 gm. alpha-bisnorcholane-3 alpha, 22-diol-3- acetate aredissolved in 18.5 ml. of absolute pyridine, 1.07 gm. toluenesulfochloride are then added. The mix is allowed to stand at roomtemperature for 3 hours. Then the reaction mixture is poured into about200 ml. ether, the organic solution is washed with hydrochloric acid andwater, dried over sodium sulfate and concentrated to dryness in vcuum.After grinding up with methanolone obtains 1.0 gm. of 20 alpha-bisnor-Sbeta-cholane-3 alpha, 22-diol-3-acetate-22 tosylate with melting point130l32 C. which after recrystallization from methanol melts at133.5l34.5 C.

(f) 550 mg. tosylate are dissolved in 7 ml. absolute acetone, then asolution of 800 mg. of NaI in 5 ml. acetone is added and heated for 3hours under reflux and with stirring. After about 3 hours, the reactionmixture is poured into water and extracted with ether. The ether phaseis washed twice with water and dried over sodium sulfate. It is thenfiltered, and the filtrate concentrated in vacuum. One obtains 550 mg.of crude 22- iodo-20 alpha-bisnor-S beta-cholane-3 alpha-ol-acetate (Icalculated=25.3%, found=24.5%

(g) The 550 mg. iodine compound from (f) of above are heated in 30 ml.freshly distilled piperidine for 3 hours under reflux, and thenconcentrated in vacuum at 25-30 C. almost to dryness. Ether is added andwashed three times with water. After drying the ether phase over sodiumsulfate, filtration and concentration of the filtrate there is obtaineda residue which, recrystallized from acetone, yields 350 mg. of22-piperidyl-20 alpha-bisnor-S beta-cholane-3 alpha-ol-acetate. Meltingpoint 117.5- 118 C.

(h) 375 mg. of the amine are boiled in 20 ml. of 4% methanolic KOH forhour in a stream of N under reflux. The mix is there acidified withacetic acid, and precipitated in water. There is obtained aftersuctioning, 300 mg. crude of 22-piperidyl-20alpha-bisnor-S-betacholane-3 alpha-o1. Recrystallized from hexane, thepure compound shows a melting point of 151-152 C.

EXAMPLE 20 (a) 2 gm. of delta -bisnorcholane-22-ol-3-one tosylate aresuspended in 28 ml. acetone, after which a solution of 5 gm. of NaI in21.5 ml. acetone is added dropwise with stirring. The reaction mixtureis heated for 3 hours under reflux and after cooling is poured into icewater. The resultant precipitate is suctioned off and dried. The crude22-iodo-delta -bisnorcholene-22-ol-3-one thus obtained is homogeneous inthe thin layer chromatogram and has an iodine content of 29.0%(calculated 28.8% with a yield of 2.1 gm.).

(b) 500 mg. of the above noted crude 22-iodine compound are dissolved in1 ml. piperidine and 12 ml. acetone and heated for 4 hours under reflux.The solvent is then extracted in vacuum and the residue is dissolved inether and washed with water. It is then dried over sodium sulfate andconcentrated. The 22-piperidyl-delta bisnorcholene-3-one thus obtainedafter recrystallization from hexane, melts at 162-164 C.

(c) mg. of the amine thus obtained are dissolved in 10 cc. dry ether andhydrochloric acid gas is then introduced. The precipitated22-piperidyl-delta -bisnor cholene-3-one-hydrochloride is now suctionedoff and dried. The melting point of the precipitate is 286-688 (3.; Clfound=Theory: 8.2%.

EXAMPLE 21 (a) The 3 alpha-acetoXy-5-bet-bisnorcholane-22-acid chlorideobtained from Example 7(a), from 1.5 gm. of 3 alpha-acetoxy-Sbeta-bisn0rcholane-22-acid is reacted with an excess of aqueousmonomethylamine solution under the conditions of Example 7(b), andprocessed. After recrystallization from acetone 1.04 gm. of 3alphaacetoxy-S beta-bisnorcholane-ZZ acid N-methylamide with meltingpoint 199 200 C. are obtained.

(b) 0.8 gm. 3 alpha-acetoxy-S beta-bisnorcholane-22- acid-N-methylamideare treated similarly as in Example 7(c) with lithium aluminum hydrideand processed. After recrystallization from acetone, 0.3 gm. ofZZ-n-methyl- 13 amino-5 beta-bisnorcholane-3 alpha-o1 with a meltingpoint of 177-178 C. is obtained.

(c) 0.13 gm. of 22-N-methylamino-5 beta-bisnorcholane-3 alpha-o1 isdissolved in 20 ml. of tetrahydrofuran and reacted with 10 ml. ethersaturated with hydrogen chloride gas. The precipitated 22-N-methylamino-5 beta-bisnorcholane-3 alpha-ol-hydrochloride is suctioned off, washedwith ether and dried. 0.1 gm. with a melting point 328-329 C.(decomposition) is obtained.

EXAMPLE 22 (a) The 3 aIpha-acetoxy-S beta-bisnorcholane-22-acid chlorideobtained analogously from Example 7(a), from 1.5 gm. 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid is reacted as in Example 8(a) in benzene with2 ml. of 1,2,3,4-tetrahydroquinoline into 3alpha-acetoxy-S-betabisnorcholane-ZZ-acid 1,2,3,4-tetrahydroquinolide.After recrystallization from hexane, 1.2 gm. with a melting point ofl76-176.5 C. are obtained.

(b) 1 gm. of 3 alpha-acetoxy-S beta-bisnorcholane-22-acid-1,2,3,4-tetrahydroquinolide are reduced as in Example 8(c), to22-(N,1,2,3,4-tetrahydroquinolino)-5 beta-bisnorcholane-3 alpha-o1.After recrystallization from hexane, 0.68 gm. with a melting point of182-183 C. are obtained.

(c) From 0.2 gm. of 22-(N-1,2,3,4-tetrahydroquinolino)-5beta-bisnorcholane-3 alpha-o1 are obtained such as in Example 8(c), 0.2gm. 22-(1,2,3,4-tetrahydroquinolino)-5 beta-bisnorcholane-3alpha-ol-hydrochloride is obtained with a melting point of 214-216 C.(decomposition).

EXAMPLE 23 (a) The 3 alpha-acetoxy-5-beta-bisnorcholane-22-acid chlorideobtained such as from Example 7 (a), from 1.5 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid is reacted as in Example 8(a), With 2 ml. of1,2,3,4-tetrahydroisoquinoline into 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid-1,2,3,4-tetrahydroisoquinolide. Afterrecrystallization from hexane, 1.4 gm. with a melting point 153-155 C.are obtained.

(b) 1.35 gm. of 3 alpha-acetoxy-S- beta-bisnorcholane-22-acid-1,2,3,4-tetrahydroisoquinolide are reduced as in Example 8(c) to22-(N,1,2,3,4-tetrahydroisoquinolino)- beta-bisnorcholane-3 alpha-o1.After recrystallization from acetone, 1.2 gm. with melting point 115-117C. are obtained.

(c) From 0.2 gm. 22-(N,1,2,3,4-tetrahydroisoquinolino)-5beta-bisnorcholane-3 alpha-o1 are obtained as in Example 8(c), 0.2 gm.of the hydrochloride with melting point 287-288 C. (decomposition).

EXAMPLE 24 (a) The 3 alpha-acetoxy-S-beta-bisnorcholane-Z2-acid chlorideobtained as in Example 7 (a), from 1.5 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid is reacted as in Example 8(a) with 2 ml. ofZ-methylpiperidine into 3 alpha-acetoxy-S-betabisnorcholane-22-acid-2methylpiperidide. After recrystallization fromhexane, 0.9 gm. with a melting point of 151-152 C., is obtained.

(b) 0.8 gm. of 3 alpha-acetoxy-S beta-bisnorcholane-22-acid-2-methylpiperidide are reduced similarly to Example 8(c), to the22-(N-2-methylpiperidino)-5 beta-bisnorcholane-2 alpha-o1. Afterrecrystallization from acetone, 0.6 gm. with melting point 136-137 isobtained.

(0) From 0.2 gm. of 22-(N-2-methylpiperidino)-5 beta-bisnorcholane-3alpha-o1 are obtained in a manner similar to Example 8(c), 0.2 gm.hydrochloride with a melting point of 320-322 C. (decomposition).

EXAMPLE 25 (a) The 3 alpha-acetoxy-S beta-bisnorcholane-22-acid chlorideobtained such as in Example 7(a) from 1.5 gm. 3 alpha-acetoxy-Sbeta-bisnorcho1ane-22-acid is reacted in a manner similar to Example8(a) with 2 ml. of 3- methylpiperidine to the 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid-3 methylpiperidide. After recrystallizationfrom hexane 1.25 gm. with a melting point of 131- 132 C. are obtained.

(b) 1.15 gm. of 3 alpha-acetoxy-S beta-bisnorcholane22-acid-3-methyl-piperidide are reduced analogously as in Example 8(c),to 22-(N-3-methylpiperidino-5 betabisnorcholane-3 alpha-o1. Afterrecrystallization from acetone, 0.9 gm. with a melting point 131-133 C.is obtained.

(c) From 0.2 gm. of 22-(N-3-methylpiperidino)-5 beta-bisnorcholane-3alpha-o1 are obtained analogously to Example Me) 0.21 gm. heptochloridewith melting point 314-315 C. (decomposition).

EXAMPLE 26 (a) 3 alpha-acetoxy-5 beta-bisnorcholane-ZZ-acid chlorideobtained as from Example 7(a), from 1.5 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane-ZZ-acid is reacted analogously as in Example 8(a),with 2 ml. of 4-methylpiperidine to 3 alpha-acetoxy-Sbeta-bisnorcholane-ZZ- -acid-4-methylpiperidide. After recrystallizationfrom hexane, 1.2 gm. with a melting point 151-152 C. are obtained.

(b) 1.1 gm. of 3 alpha-acetoxy-S beta-bisnorcholane-22-acid-4-methylpiperidide are reduced analogously to Example 8(c), to22-(N-4-methylpiperidino)-5 beta-bisnorcholane-3 alpha-01. Afterrecrystallization from acetone, 0.8 gm. with a melting point of 138-139C. is obtained.

(c) From 0.2 gm. 22-(N-4-methylpiperidino)-5betabisnorcholane-3-alpha-ol are obtained in a manner analogous toExample 8(0), 0.19 gm. hydrochloride with a melting point of 320-321 C.(decomposition).

EXAMPLE 27 (a) The 3 alpha-acetoxy-S beta-bisnorcholane-22-acid chlorideobtained as in Example 7(a) from 1.5 gm. of alpha-acetoxy-Sbeta-bisnorcholane-22-acid is reacted as in Example 8(a) with 2 ml. of2, 6-dimethyl-piperidine to 3 alpha-acetoxy-Sbeta-bisnorcholane-22-acid-2, 6-dimethyl-piperidide. Afterrecrystallization from hexane 1.3 gm. with a melting point 162-163 C.are obtained.

(b) 1.2 gm. of 3 alpha-acetoxy-S beta-bisnorcholane- 22-acid-2,G-dimethyl-piperidide are reduced analogously to Example 8(c), to22-(N-2, 6-dimethyl-piperidino)-5 beta-bisnorcholane-3 alpha-ol.Yield=0.6 gm.

(c) From 0.2 gm. of 22-(N-2, 6 dimethylpiperidino)- 5beta-bisnorcholane-3 alpha-o1 are obtained as in Example 8(c) .018 gm.of the hydrochloride with melting point 295-297 C. (decomposition)EXAMPLE 28 As in Example 8(d) 210 mg. of 22-(N-piperidyl)-5beta-bisnorcholane-3 alpha-016,4,S-trihydroxybenzoate are obtained from200 mg. of 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1 and3,4,5-trihydroxybenzoic acid. Melting point 227-228 C. (decomposition)EXAMPLE 29 In a manner similar to Example 8(d), 205 mg. of 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-ol-Z-bromobenzoate areobtained from 200 mg. 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1and 2 bromobenzoic acid. Melting point -191 C.

EXAMPLE 30 220 mg. of 22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha01-2,3,4-trihydroxybenzoate are obtained in a manner similar to example8(d) from 200 mg. 22-(N- piperidyl)-5 beta-bisnorcholane-3 alpha-o1 and2,3,4-trihydroxybenzoic acid. Melting point 203-2035 C. (decomposition).

EXAMPLE 31 Analogous to Example 8(d) 210 mg. of 22-(N-piperidyl)-5beta-bisnorcholane-3 alpha-ol-Z, 6-dihydrozybenzoate are obtained from220 mg. 22-(N-piperidyl)-5 beta- EXAMPLE 32 Analogous to Example 8(d)210 mg. of 22-(N-piperidyl) 5 beta-bisnorcholane-3alpha-ol-2,4-dihydroxybenzoate are obtained from 200 mg. of22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1 and2,4-dihydroxybenzoic acid. Melting point 195196 C.

EXAMPLE 33 210 mg. of 22-(N-piperidyl)-5 beta-bisnorcholane-3alpha-ol-2-chlorobenzoate are obtained in a manner set forth in Example8(d) from 200 mg. of 22-(N-piperidyl) 5 beta-bisnorcholane-3 alpha-o1and 2-chlorobenzoic acid. Melting point 185-187 C.

EXAMPLE 34 (a) To 10 gm. of delta -bisnorcholene-11 beta-ol-3-one- 22acid methyl ester (prepared from delta -bisnorcholene- 3-one-33-acid bymicrobiological hydroxylation and subsequent esterification) in 1.2liters of acetone are slowly dropped 11 ml. of Jones reagent at 150 C.The mix is continuously stirred for one more hour. The excess reagent isdestroyed by the addition of methanol and stirring of the reactionmixture in a 5-fold amount of ice water. The resultant precipitatedcrude delta -bisnorcholene-3,11'dione-22-acid methyl ester is suctionedoff and recrystallized from isopropyl ether. The yield=9.1 gm. Meltingpoint: 171-171.5 C.

(b) 9 gm. of delta -bisnorcholene-3,11-dione-22-acid methyl ester aredissolved in 450 ml. methanol, and reacted with 450 ml. 30% aqueoussodium hydroxide with heating for one hour under reflux. The mix isallowed to cool and with stirring is poured into ice water, acidified.The crude delta -bisnorcholene-3,11-dione-22-acid is suctioned off.After recrystallization from isopropanol, 6.35 gm. with a melting pointof 249251 C. are obtained.

Analogously to Example 8(a) 0.73 gm. of delta*-bisnorcholene-3,11-dione-22-acid piperidide is obtained from 2 gm. ofdelta -bisnorcholene-3,l1-dione-22-acid after recrystallization fromacetone. Melting point 241- 243 C.

(d) 0.65 gm. of 22-(N-piperidyl)-delta -bisnorcholene- 3,11-diol made asin Example 8(b) are obtained from 1.2 gm. deltabisnorcholene-3,ll-dione-22-acid piperidide. The hydrochloride has amelting point of 289291 C. (decomposition).

(e) 0.65 gm. of 22-(N-piperidyl)-delta -bisnorcholene- 3,11 beta-diolare dissolved in 35 ml. benzene and reacted with 0.85 gm. of aluminumisopropylate and 3.5 ml. ace tone and stirred for 48 hours at roomtemperature. After such time, the reaction mixture is distilled withsteam until no more oil comes over. After cooling to 50 C., 0.6 ml. ofglacial acetic acid are added. One then allows this mix to cool to roomtemperature wherein the reaction product is picked up inmethylenechloride. After washing with water, drying and concentrationunder reduced pressure, the crude 22-(N-piperidyl)-delta-bisnorcholene-11-beta-ol-3-one is obtained, which, afterrecrystallization from acetone, melts-at 217218 C. Yield: 0.35 gm.

(f) Analogously to Example 8(0), 0.21 gm. of the hydrochloride areobtained from 0.22 gm. of 22-(N-piperidyl) delta -bisnorcholene-11beta-ol-3-one, Melting point 298-300 C. (decomposition).

EXAMPLE 35 (a) Analogously to Example 9(b), 10.5 gm. of22-aminobeta-bisnorcholane3-one-are obtained from 1.6 gm. of 22-amino-5beta-bisnorcholane-3 alpha-o1 after purification through preparativelayer chromatography.

(b) 1 gm. of 22-amino-5 beta-bisnorcholane-3-one is dissolved in 120 ml.of tetrahydrofuran and then dry hydrogen chloride is led into thesolution with ice cooling.

16 The resultant precipitated hydrchloride is suctioned off, dried andstirred with glacial acetic acid at room tem perature. There is thusobtained 0.85 gm. of the hydrochloride which clearly .beigns todecompose at 330 C.

Example 36 (a) 1.8 gm. of 5 beta-bisnorcholane-3, 22-diol-3-acetate(prepared from the corresponding aldehyde by hy drogenation with Raneynickel in ethanol, pure melting point from isopropyl ether -141.5 C.)are dissolved in 18 cc. of pyridine and reacted with 1.13 gm. ofptoluene sulfo-acid chloride and allowed to stand at room temperaturefor 3 hours. After the addition of ether, this solution is successivelywashed with water, hydrochloric acid and water, dried over sodiumsulfate and then concentrated to dryness. The crude produce thus formed,is reacted with methanol and the 5 beta-bisnorcholane-3,22-diol-3-acetate-22-tosylate which then crystallizes out is suctionedoff. Yield=1.25 gm.; melting point 9798 C.

(b) To 1.2 gm. 5 beta-bisnorcholane-3,22-diol-3-acetate-22-tosylatedissolved in 16 cc. acetone are added 1.92 gm. sodium iodide (dissolvedin 10 cc. acetone) and heated for 3 hours (under reflux conditions). Thecooled reaction mixture, after dilution with ice water, is extractedwith ether. After washing with water, the ether solution is dried andconcentrated in vacuum to dryness. The crude22-iodo-5-beta-bisnorcholane-3 a1pha-ol-3 acetate (1.1 gm.) thusobtained, exhibits an iodine content of 25.8% (theory 26.1%).

(c) To 1.07 gm. of crude 22-iodo-5 beta-bisnorcholane-3 alpha-ol-3acetate dissolved in 15 cc. benzene are added 360 mg. imidazol and thereaction mixture is heated for 18 hours under reflux. Then it is dilutedwith benzene, the solution washed with water, then dried over sodiumsulfate and concentrated to dryness in vacuum. After recrystallizationfrom methanol over charcoal, the residue yields 600 mg. of22-N-imidazolyl-5 beta-bisnorcholane-3 alpha-o1 3 acetate with meltingpoint 235-236 C.

(d) 400 mg. of 22-N-irnidazoly1-5 beta-bisnorcholane- 3 alpha ol3-acetate are heated with 20 cc. of 4% methanolic potassium hydroxidefor 45 minutes under reflux. The cooled reaction solution is poured intowater and extracted with methylenechloride. After washing with water anddrying, the methlenechloride solution is concentrated in vacuum todryness. The crude 22-N- imidazolyl-S beta-bisnorcholane 3 alpha-o1(pure melting po nt from isopropyl ether, 187-187.5 C.), is dis solvedin 5 cc. absolute tetrahydrofuran and reacted with 30 cc. ether which issaturated with'gaseous hydrochloric acid. The 22-N-imidazolyl-5beta-bisnorcholane-3 alphaol-hydrochloride that precipitates during thisreaction is suctional ofl. and washed with ether. The yield=250 mg.Melting point 240241 C. Cl calculated=8.43, found=8.62.

Example 37 (a) The 3 alpha-acetoxy 5 beta-bisnorcholane-22- acidchloride obtained as from Example 7(a), from 2 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane-Z2-acid is reacted as in Example 11 (a), with 2 ml.of benzylamine to 3 alpha-acetoxy-Sbeta-bisnorcholane-Z2-acidbenzylamide. After recrystallization fromisopropanol, 1.5 gm. with melting point 226227 C. are obtained.

(b) 1.5 gm. 3 alpha-acetoxy-S beta-bisnorcholane-22- acid benzylamideare reduced analogously to Example 11(b) to 22 (N benzylamino)-5beta-bisnorcholane-3 alpha-o1. After processing and recrystallizationfrom acetone/hexane 1.1 gm., with melting point 8999 C. are obtained.

(c) From 0.9 gm. of 22-(benzylamino)-5 beta-bisnorcholane-3 alpha-o1 areobtained by dissolving in ether, introducing dry hydrogen chloride,suctioning the precipitate and treated with acetate 0.8 gm.hydrochloride with melting point 280282 C. (decomposition).

1 7 Example 38 (a) The 3 alpha-acetoxy-S beta-bisnorcholane-22-acidchloride obtained as in Example 7(a), from 3 gm. of 3 alpha-acetoxy-Sbeta-bisnorcholane 22-acid is reacted analogously to Example 11(a) with3 ml. of isopropylamine to 3 alpha-acetoxy-S beta-bisnorcholane-22-acidisopropylamide. After recrystallization from acetone 2.3 gm. withmelting point 205-206 C. are obtained.

(b) 2.3 gm. 3 alpha-acetoxy-S beta-bisnorcholane-ZZ- acid isopropylamideare reduced analogously to Example 11(b), reaction time 5 days, withlithium aluminum hydride to 22-(N-isopropylamino)-S beta-bisnorcholane-3alpha-o1. After separation of the contaminations by treatment withether, 1.3 gm. of 22-(N-isopropylamino)5 beta-bisnorcholane-3 alpha-o1are obtained.

(c) From 1.3 gm. 22-(N-isopropy1amino)5 beta-bisnorcholane-3 alpha-o1are obtained according to Example 37(c), 1.1 gm. of hydrochloride withmelting point 305-307 C. (decomposition).

From the foregoing description and illustrative examples of ourinvention, it will be noted that various methods and modifications maybe adopted without departing from the spirit and scope of the inventionas claimed.

We claim:

1. A medication, containing as active ingredient, a 5- B-bisnorcholanecompound of the general formula:

wherein each of R and R is independently selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, substituted alkyl, aryland aralkyl, or R and R taken to gether form a heterocyclic ringselected from piperidine, morpholine, pyrrolidine, imidozole,substituted piperidine, substituted morpholine substituted pyrrolidine,substituted imidazole, and derivatives thereof; Z is selected from =CH='CH(0H), and =O= O; X is selected from =CH =CH(OH), ===CH(O acyl),50:0; and C C -C and C O, represent single or double bonds; and ammoniumsalts thereof; R R X and Z being so'selected that the S-B-bisnorcholanecompound is a member selected from the group consisting of 3alpha-acetoxy-ZZ-(N-piperidyl)-5-beta-bisnorcholane;

22-(-N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1;

22-(N-piperidy1)-5 beta-bisnorcholane-3 alpha-olhydrochloride;

22-(N-piperidyl)-5 beta-bisnorcholane-3-one;

22-(N-piperidyl)-5 beta-bisnorcholane-3 onehydrochloride;

22-(N-piperidyl) -5 beta-bisnorcholane;

22-(N-piperidyl)-5 beta-bisnorcholane-hydrochloride;

3 alpha-acetoxy-22-(N-morpholino)-5-beta-bisnorcholane;

3 alpha-acetoxy-ZZ-(N-morpholino) -5 beta-bisnorcholane-hydrochloride;

22-(N-morpholino)-S beta-hisnorcholane-B alpha-o1;

22- (N-morpholino -5 beta-bisnorcholane-3 alpha-olhydrochloride;

3 alpha-acetoxy-ZZ- (N-pyrrolidino -5-beta-bisnorcholane;

22-(N-pyrrolidino)-5-beta-bisnorcholane-3 alpha-o1;

22-(N-pyrrolidino) -5 beta-bisnorcholane-3 alpha-olhydrochloride;

3 alpha-acetoxy-22-(N-diethyl-amino)-5-beta-bisnorcholane;

22-(N-diethylamino)-5 beta-bisnorcho1ane-3 alpha-o1;

22-(N-diethyla-mino)-5 beta-bisnorcholane-3 alpha-o1- hydrochloride;

22 amino-5 beta-bisnorcholane-3 alpha-o1;

22 amino-5 beta bisnorcholane-3 alpha-ol-hydrochloride;

22-(N-piperidyl)-S beta-bisnorcholane-3 beta-o1;

22-(phenylarnino)-5 beta-bisnorcholane-3 alpha-o1;

22-(phenylamino)-5 beta-bisnorcholane-3 alpha-olhydrochloride;

22-amino-5 beta-bisnorcholane;

22-amino-5 beta-bisnorcholane-hydrochloride;

22-(N-piperidyl)-delta -bisnorcholene-3-one;

22- N-piperidyl) -delta -bisnorcholene-3 -onehydrochloride;

22-(N-piperidino -5 beta-bisnorcholane-3 alpha-olmethiodide;

ZZ-N-methylamino-Sjabeta-bisnorcholane-3 alpha-o1;

ZZ-N-methylamino-S beta-bisnorcholane-3 alpha-o1- hydrochloride;

22-(N-1,2,3,4-tetrahydroquinolino)-5 beta-bisnorcholane-3 alpha-o1;

22-(n-1,2,3,4-tetrahydroquinolino) -5 beta-bisnorcholane- 3alpha-ol-hydrochloride;

22-(N-1,2,3,4-tetrahydroisoquinolino) -5 betabisnorcholane-3 alpha-o1;

22-(N-1,2,3,4-tetrahydroisoquinolino) -5 beta-bisnorcholane-3alpha-ol-hydrochloride;

22- (N-Z-methylpiperidino) -5 beta-bisnorcholane-3 alpha-o1;

22-(N-Z-methylpiperidino)-5 beta-bisnorcho1ane-3 alpha-ol-hydrochloride;

22-(N-3-methylpiperidino)-5 beta-bisnorcholane-3 alpha-o1;

22- (N -3-methy1piperidino -5 beta-bisnorcholane-3alpha-ol-hydrochloride;

22-(4-methylpiperidino)-5 beta-bisnorcholane-B alpha-o1;

2%(N-4-methylpiperidino)-5 beta-bisnorcholane-3 alpha-ol-hydrochloride;

22-(N-2,6-dimethy1piperidino)-5 beta-bisnorcholane-3 alpha-o1;

22-(N-2,6-dimethylpiperidino)-5 beta-bisnorcholane-3alpha-ol-hydrochloride;

22-(N-piperidyl)-5 beta-bisnorcholane-3 alpha-o1-3,4,5-trihydroxybenzoate;

22-(N-piperidyl)-5 beta-bisnorcholane-3 beta-ol-2,3,4-trihydroxybenzoate;

22-(N-piperidyl)-S beta-bisnorcholane-3 alpha-o1-2,6-

dihydroxybenzoate;

22-(N-piperidyl)-5 beta-bisnorcho1ane-3 alpha-ol-Z- chlorobenzoate;

22- (N-piperidyl) -delta -bisnorcholene-3,1 1 beta-diol;

ZZ-(N-piperidyl)-delta -bisnorcho1ene-11 beta-ol-3 -one;

22-(N-piperidyl) delta -bisnorcholene-l l beta-ol-3-onehydrochloride;

22-amino-bisnoroholane-3-one;

22-amino bisnorcholane-3-one-hydrochloride;

22-N-imidazolyl-5 beta-bisnorcholane-3 alpha-o1;

22-N-imidazolyl-5 beta-bisnorcholane-3 alpha-olhydrochloride;

22-(N-isopropylamino)-5 beta-bisnorcholane-3 alpha-o1;

22-(N-isopropylamino) -5-beta-bisnorcholane-3 alpha-o1- hydrochloride;

22-(=N-benzylamino)-5 beta-bisnorcholane-3 alpha-o1;

22-(N-benzylamino) -5 beta-bisnoroholane-3 alpha-olhydrochloride;

and an inert, pharmaceutically accceptable carrier combined with saidactive ingredient.

2. A compound as set forth in claim 1 and known as ZZ-(N-piper-idyD-Sbeta-bisnorcholane-3 alpha-o1 and its salts selected from the groupconsisting of hydrochloride, 2,6-dihydroxy-benzoate, methiodide,3,4,5-trihydroxy-benzoate, 2,3,4-trihydroxy-benzoate, and2-chlorobenzoate.

3. A compound as set forth in claim 1 and known as 22-(N-piperidyl)-5beta-bisnorcholane-3-one and its hydroc-hloride.

4. A compound as set forth in claim 1 and known as 22-(N-morpholin0)-5beta-bisnorcholane-3-alpha-ol, and its hydrochloride.

5. A compound as set forth in claim 1 known as 22- amino'5beta-bisnorcholane-3-alpha-ol, and its hydrochloride.

6. A compound as set forth in claim 1 known as 22- amino-Sbeta-bisnorcholane, and its hydrochloride.

7. A compound as set forth in claim 1 known as 22- N-methylamino-Sbeta-bisnorcholane-3-alpha-ol, and its hydrochloride.

8. A compound as set forth in claim 1 known as 22-(N-1,2,3,4-tetrahydroisoquinolino)-5 beta-bisnorcholane- 3 alpha-01, andits hydrochloride.

9. A compound as set forth in claim 1 known as 22- N-Z-methylpiperidino-5 b eta-bisnorcholane-3 -alpha-ol, and its hydrochloride.

10. A compound as set forth in claim 1 known as 22-(N-3-methylpiperidino)-5 beta-bisnorcholane-3 alpha-o1, and itshydrochloride.

11. A compound as set forth in claim 1 known as 22-(N-4-methylpiperidino)-5 beta-bisnorcholane-3 alpha-o1, and itshydrochloride.

12. A compound as set forth in claim 1 known as 22-(N-2,6dimethylpiperidino)-5 beta-bisnorcholane-3 alpha-o1, and itshydrochloride.

13. A compound as set forth in claim 1 known as 22- (N-piperidyl)-delta-bisnorcholene 3,11 beta-ol-3-one, and its hydrochloride.

14. A compound as set forth in claim 1 known as22-amino-bisnorcholane-3-one, and its hydrochloride.

15. A compound as set forth in claim 1 known as 22- (N-isopropylamino)-5beta-bisnorcholane-3 alpha-o1, and its hydrochloride.

16. A compound as set forth in claim 1 known as 22- (N-diethylamin0)-5betabisnorcholane-3 alpha-o1, and its hydrochloride.

17. A compound as set forth in claim 1 known as 22- (N-pyrrolidino)-5beta-bisnorcholane-3 alpha-o1, and its hydrochloride.

18. A compound as set forth in claim 1 and known as 22-(N-piperidyl)-5beta bisnorcholane, and its hydrochloride.

References Cited UNITED STATES PATENTS 2,886,564 5/1959 Holysz 260-239.52,697,107 12/1954 Ruschig et a1. 260--397.2 3,038,912 6/1962 Nysted260397.1 3,342,811 9/1967 Sarel et al. 260--239.5

ELBERT L. ROBERTS, Primary Examiner US. Cl. XJR.

